Despite the current FDA-approved therapies, the prevalence of type 2 diabetes (T2D) and various other metabolic diseases is reaching epidemic proportions. Globally, 387 million people have overt diabetes, and the prevalence of impaired fasting glucose (precursor to T2D referred to as ?pre-diabetes?) is 26% of the US population. Consequently, T2D and its frequent co-morbidities (high triglycerides, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis [NAFLD/NASH], and cardiovascular disease) increasingly account for a large proportion of global end-stage renal and liver failure, limb amputations, blindness, myocardial infarctions, and strokes. To address this highly unmet need, Potrero Hill Therapeutics (?PHT?) has discovered highly- potent, drug-like, and orally-active small molecule inhibitors of dihydroceramide desaturase-1 (DES1), a key enzyme which catalyzes the final step in the de novo formation of ceramides, molecules which drive insulin resistance, high triglycerides, fatty liver, and atherosclerosis when produced in excess. This work has been partially funded through an SBIR Phase 1 grant, and in this Phase 2 grant, PHT will continue preclinical characterization and early development of its lead DES1 inhibitor candidate: 1) We will comprehensively profile the therapeutic activity of our lead DES1 inhibitor candidate in a well-validated mouse model of insulin resistance/T2D, and compare its potency to those of several other candidate DES1 inhibitors; 2) We will conduct pilot safety studies of our most potent DES1 inhibitor candidate in order to determine safety margins and identify potential off-target activities; and 3) We will continue medicinal chemistry to generate several backup DES1 inhibitors. Ultimately, successful completion of these aims will yield a clinical development candidate that is ready for IND-enabling activities, including GMP manufacturing and pivotal GLP toxicology/safety studies, paving the way for clinical trials in humans.